Project Summary/Abstract Charles Kyriakos Vorkas, MD is a Fellow in Infectious Diseases at Weill Cornell Medicine (WCM) and a member of the Glickman Laboratory, Memorial Sloan Kettering Cancer Center (MSKCC) whose research interests focus upon Innate immunity during Mycobacterium tuberculosis (Mtb) infection. He plans to pursue a career as a physician-scientist in the field of Tuberculosis (TB) immunology. This proposal describes a five-year training program that will provide the candidate with the knowledge and technical skills to achieve this goal. In addition to intensive laboratory-based experimental training, the proposal includes regular meetings with an advisory committee of experts, active involvement in academic conferences, and formal coursework. At the end of the period of support, the candidate will be prepared to embark on a career as an independent investigator. Little is known about the host factors that influence clearance of Mtb infection, control of latency or progression to active disease. The candidates' work will focus on the role of mucosal- associated invariant T (MAIT) cells in innate immunity to Mtb using an ex vivo MAIT cell activation assay in Haitian donors. MAIT cells are MR1-restricted lymphocytes that recognize bacterially- derived Vitamin B metabolites and data suggest that they act early at mucosal surfaces during Mtb infection. The candidate will investigate immune correlates of resistance to Mtb infection through analysis of three Haitian cohorts: (1) active TB patients (2) healthy household contacts of TB patients and (3) healthy community volunteers without reported exposure. The candidate will also screen synthetic MR1 ligand analogs for effects on MR1 regulation and MAIT activation and test if they can restrict bacterial growth through priming MAIT cells in a monocyte-derived macrophage co-culture model of Mtb infection. This study proposes to identify immune correlates of innate resistance to Mtb infection, which may have direct translational applications for TB immunotherapy or vaccine design.